Project Summary/Abstract: The overarching goal of this five-year proposal is development of the candidate into an independent investigator leading a robust translational research program in the field of primary immune deficiencies. The candidate is optimally positioned, through his background of structured training in clinical immunology and extensive research experience in human immunobiology, to fully realize the benefits of a NIH mentored career development award. The proposal promotes a line of investigation leading directly to the introduction of new therapies specifically tailored for common variable immune deficient patients with autoantibody-mediated autoimmune diseases. The candidate has assembled an outstanding team of mentors uniquely qualified to assist in accomplishing his long-term research goals. The team includes Eric Meffre, PhD, a pioneer in the field of B cell tolerance, Charlotte Cunningham-Rundles, MD PhD, an international expert in common variable immune deficiency and Richard Lifton, MD PhD, a leader in human genetics with specific strength in high-throughput approaches. A less formal advisory committee of highly-regarded medical scientists, Drs. Pober, Hafler and Craft have each advised the candidate on aspects of his proposal and will provide additional ongoing scientific/career advice. The candidate has also proposed a program of didactic coursework and hands-on experiences designed to promote investigator independence at the conclusion of the award period. Research will focus on regulatory T cell (Treg) suppression of autoantibody secretion in humans. Preliminary data suggests that Tregs from healthy donors do not interact with B cells directly but control them through a T effector intermediary. In CVID patients with autoimmune cytopenias there is loss of this control due to Treg dysfunction and the abundance of circulating T effector population, resembling follicular T cells (Tfh), that drives autoantibody secretion. Specific aims of the proposal include: 1) investigating the molecular mechanism employed by Tregs to influence B cells in vitro 2) determining how Tfh-like cells from CVID patients with ITP differ from phenotypicall similar populations in primary ITP patients and healthy donors at the gene expression level and also functionally in terms of how they shape the reactivities of secreted antibodies, and 3) demonstrating the effect of IL-2 restored CVID Tregs on Tfh-like-driven autoantibody secretion. Together the aims of the proposal have been designed to generate pre-clinical data to support a clinical trial of low-dose IL-2 in CVID patients with autoimmune cytopenias. In addition to their own merits, the candidate and his proposal are further enriched by the ideal academic environment and extensive resources provided by Yale University's Departments of Immunobiology, Genetics and Pediatrics. The candidate has access to rare patient samples through his own Yale CVID cohort and the nearby CVID cohort of Dr. Cunningham-Rundles, the largest in North America, if not the world. In brief, this application proposes a plan of research that is relevant, important and achievable. It is a plan designed to culminate in the candidate establishing an independent patient- oriented research program in an academic setting.